EGFR proteolysis targeting chimeric molecules and associated methods of use

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

What is claimed is: 
     
       1. A bifunctional compound having the chemical structure:
   PTM-Linker-ULM, 
 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or solvate, 
 
       wherein:
 (i) the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds a cereblon E3 ubiquitin ligase and has a chemical structure selected from: 
 
       
         
           
           
               
               
           
         
         wherein:
 W is selected from the group consisting of CH 2 , CHR, C═O, SO 2 , NH, and N-alkyl; 
 each X is independently selected from the group consisting of absent, O, and S; 
 Y is selected from the group consisting of CH 2 , —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; 
 Z is selected from the group consisting of absent, O, and S; 
 G and G′ are independently selected from the group consisting of H, optionally substituted alkyl, OH, R′OCOOR, R′OCONRR″, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′; 
 Q 1 , Q 2 , Q 3 , and Q 4  represent a carbon C substituted with a group independently selected from H, R, N or N-oxide; 
 A of the ULM is independently selected from the group H, alkyl, cycloalkyl, Cl and F; 
 n is an integer from 1 to 10; 
 R is selected from the group consisting of: —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O) n R″, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF 3 , —CN, —NR′SO 2 NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO 2 )NR′R″, —SO 2 NR′ COR″, —NO 2 , —CO 2 R′, —C(C═N—OR′) R″, —CR′═CR′ R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF 5  and —OCF 3 , wherein one R is covalently joined via the linker (L) to the PTM; 
 R′ and R″ are independently selected from the group consisting of a H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, —C(═O)R, and optionally substituted heterocyclyl; and 
    represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; 
 
         (ii) the PTM is a small molecule protein targeting moiety selected from (a), (b), (c), or (d), wherein: 
         (a) PTM according to the structure of formula XIII: 
       
       
         
           
           
               
               
           
         
         wherein:
 A of formula XIII is a saturated or unsaturated 4-8 atom carbocyclic or heterocyclic ring comprising 1-7 heteroatoms; 
 R k1  is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k2  is selected from H, alkyl, cycloalkyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k3  and R k4  are independently selected from H, hydroxyl, alkyl, alkoxy, aryl, —SO 2 R k2 , or halogen, wherein the said hydroxyl, alkyl, aryl or alkoxy is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and 
 X is N or CH or C with a double bond to the neighbor atom in the ring, 
 wherein the PTM is coupled via the linker (L) to the ULM; 
 
         (b) the PTM according to the structure of formula XV: 
       
       
         
           
           
               
               
           
         
         wherein:
 R k8  is selected from H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k9  is selected from H, alkyl, or cycloalkyl, wherein the said alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and 
 R k10  is selected from H, alkyl, alkylsulfone, alkylcarboxamide or aryl, wherein the said alkyl or aryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano, 
 wherein the PTM is coupled via the linker (L) to the ULM; 
 
         (c) the PTM according to the structure of formula XVI: 
       
       
         
           
           
               
               
           
         
         wherein:
 R k11  is selected from H, alkyl, alkoxy, —C(O)NHR, wherein R is selected from H, alkyl, cycloalkyl or a saturated heterocycle with 4-6 ring atoms; 
 R k12  is selected from H, linear or branched alkyl, aryl, cycloalkyl or heteroaryl, wherein the alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k13  is selected from H, alkyl, —C(O)NHR, —C(O)R, —S(O) 2 R, wherein R is H, alkyl or cycloalkyl, which can be further substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano; and 
 X is N or CH, 
 wherein the PTM is coupled via the linker (L) to the ULM; or 
 
         (d) the PTM according to the structure of formula XVII: 
       
       
         
           
           
               
               
           
         
         wherein:
 R k14  is selected from H, N, alkyl, alkoxy, —C(O)NHR, wherein R is selected from H, alkyl, cycloalkyl or a saturated heterocycle with 4-6 ring atoms; 
 R k15  is selected from H, linear or branched alkyl, aryl, cycloalkyl or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k16  is selected from H, alkyl or cycloalkyl, which is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano; and 
 R k17  is selected from H, halogen, CN, 
 wherein the PTM is coupled via the linker (L) to the ULM; and 
 
         (iii) the linker (L) is a chemical linking moiety covalently coupling the ULM and the PTM and comprises a chemical structural unit represented by the formula:
   -(A L ) q -, 
 
         wherein:
 (A L ) q  is a group which is connected to at least one of a ULM, a PTM moiety, or a combination thereof; 
 q is an integer greater than or equal to 1; 
 each A L  is independently selected from the group consisting of CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L1 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1  and/or R L2  groups, C 3-11 heterocyclyl optionally substituted with 0-6 R L1  and/or R L2  groups, aryl optionally substituted with 0-6 R L1  and/or R L2  groups, heteroaryl optionally substituted with 0-6 R L1  and/or R L2  groups, where R LI  or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R L5  groups; and 
 R L1 , R L2 , R L3 , R L4  and R L5  are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11  cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8  cycloalkyl) 2 , N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , and NH SO 2 NH 2 . 
 
       
     
     
       2. The compound according to  claim 1 , wherein the PTM comprises the structure of formula XIII: 
       
         
           
           
               
               
           
         
       
       wherein:
 A of formula XIII is a saturated or unsaturated 4-8 atom carbocyclic or heterocyclic ring comprising 1-7 heteroatoms; 
 R k1  is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k2  is selected from H, alkyl, cycloalkyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k3  and R k4  are independently selected from H, hydroxyl, alkyl, alkoxy, aryl, —SO 2 R k2 , or halogen, wherein the said hydroxyl, alkyl, aryl or alkoxy is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and 
 X is N or CH or C with a double bond to the neighbor atom in the ring, 
 wherein the PTM is coupled via the linker (L) to the ULM. 
 
     
     
       3. The compound according to  claim 1 , wherein the PTM comprises the structure of formula XV 
       
         
           
           
               
               
           
         
       
       wherein:
 R k8  is selected from H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k9  is selected from H, alkyl, or cycloalkyl, wherein the said alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and 
 R k10  is selected from H, alkyl, alkylsulfone, alkylcarboxamide or aryl, wherein the said alkyl or aryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano, 
 wherein the PTM is coupled via the linker (L) to the ULM. 
 
     
     
       4. The compound according to  claim 1 , wherein the PTM comprises the structure of formula XVI 
       
         
           
           
               
               
           
         
       
       wherein:
 R k11  is selected from H, alkyl, alkoxy, —C(O)NHR, wherein R is selected from H, alkyl, cycloalkyl or a saturated heterocycle with 4-6 ring atoms; 
 R k12  is selected from H, linear or branched alkyl, aryl, cycloalkyl or heteroaryl, wherein the alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k13  is selected from H, alkyl, —C(O)NHR, —C(O)R, —S(O) 2 R, wherein R is H, alkyl or cycloalkyl, which can be further substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano; and 
 X is N or CH, 
 wherein the PTM is coupled via the linker (L) to the ULM. 
 
     
     
       5. The compound according to  claim 1 , wherein the PTM comprises the structure of formula XVII 
       
         
           
           
               
               
           
         
       
       wherein:
 R k14  is selected from H, N, alkyl, alkoxy, —C(O)NHR, wherein R is selected from H, alkyl, cycloalkyl or a saturated heterocycle with 4-6 ring atoms; 
 R k15  is selected from H, linear or branched alkyl, aryl, cycloalkyl or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; 
 R k16  is selected from H, alkyl or cycloalkyl, which is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano; and 
 R kl7  is selected from H, halogen, CN, 
 wherein the PTM is coupled via the linker (L) to the ULM. 
 
     
     
       6. The compound according to  claim 1 , wherein the linker (L) is coupled to the PTM via R k1 , R k2 , R k3 , R k4 , R k8 , R k9 , R k10 , R k11 , R k12 , R k13 , R k14 , R k15 , R k16 , or R k17 . 
     
     
       7. The compound according to  claim 2 , wherein the linker (L) is coupled to the PTM via R k1 , R k2 , R k3 , or R k4 . 
     
     
       8. The compound according to  claim 3 , wherein the linker (L) is coupled to the PTM via R k8 , R k9 , or R k10 . 
     
     
       9. The compound according to  claim 4 , wherein the linker (L) is coupled to the PTM via R k11 , R k12 , or R k13 . 
     
     
       10. The compound according to  claim 5 , wherein the linker (L) is coupled to the PTM via R k14 , R k15 , R k16 , or R k17 . 
     
     
       11. The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 1 , wherein the ULM has a chemical structure represented by: 
       
         
           
           
               
               
           
         
       
       wherein:
 W is independently selected from the group CH 2 , C═O, NH, and N-alkyl; 
 A is independently selected from a H, methyl, optionally substituted alkyl; 
 n is an integer from 1 to 4; and 
    represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. 
 
     
     
       13. The compound of  claim 1 , wherein the linker (L) comprises a group represented by a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein m, n, o, p, q, and r, are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, with the proviso that when m, n, o, p, q, or r is zero, there is no N—O or O—O bond, R is selected from the group H, methyl and ethyl, and X is selected from the group H and F. 
     
     
       14. The compound of  claim 1 , wherein the linker (L) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6. 
     
     
       15. The compound of  claim 1 , wherein the linker (L) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 
     
     
       16. The compound of  claim 1 , wherein the linker (L) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       17. The compound of  claim 1 , wherein the linker (L) has a chemical structure selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 W L1  and W L2  are each independently a 4-8 membered ring with 0-4 heteroatoms, independently optionally substituted with H, halo, OH, CN, CF 3 , optionally substituted linear or branched C 1 -C 6  alkyl, optionally substituted linear or branched C 1 -C 6  alkoxy, or groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 
 Y L1  is each independently a bond, optionally substituted linear or branched C 1 -C 6  alkyl and optionally one or more C atoms are replaced with O; or optionally substituted linear or branched C 1 -C 6  alkoxy; 
 n is 0-10; and 
 
       
         
           
           
               
               
           
         
       
       indicates the attachment point to the PTM or ULM moieties. 
     
     
       18. The compound of  claim 1 , wherein the linker (L) has a chemical structure selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 W L1  and W L2  are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1-6  alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each independently optionally substituted with is independently a H, halo, OH, CN, NH 2 , NR Y1 R Y2 , CF 3 , hydroxyl, nitro, C═CH, C 2-6  alkenyl, C 2-6  alkynyl, optionally substituted linear or branched C 1 -C 6  alkyl, optionally substituted linear or branched C 1 -C 6  alkoxy, OC 1-3 alkyl optionally substituted by 1 or more —F, or groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 
 Y L1  is each independently a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C═O, C═S, SO, SO 2 , optionally substituted linear or branched C 1 -C 6  alkyl and optionally one or more C atoms are replaced with O; optionally substituted linear or branched C 1 -C 6  alkoxy; 
 Q L  is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R Q , each R Q  is independently H, linear or branched C 1-6  alkyl optionally substituted by 1 or more halo or C 1-6  alkoxyl, or 2 R Q  groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; 
 R YL1  R YL2  are each independently H, OH, linear or branched C 1-6  alkyl optionally substituted by 1 or more halo or C 1-6  alkoxyl, or R 1 , R 2  together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; 
 n is 0-10; and 
 
       
         
           
           
               
               
           
         
       
       indicates the attachment point to the PTM or ULM moieties. 
     
     
       19. The compound of  claim 1 , wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units. 
     
     
       20. A composition comprising an effective amount of a compound of  claim 1 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       21. The composition of  claim 20 , wherein the composition further comprises at least one of an additional bioactive agent or an additional compound of  claim 1 . 
     
     
       22. The composition of  claim 21 , wherein the additional bioactive agent is an anti-cancer or anti-inflammatory agent. 
     
     
       23. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       24. A method of treating squamous-cell carcinoma of the lung comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
       25. A compound selected from the group consisting of: